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2005 SABCS Review: Surgery, Radiation, and Prevention

2005 SABCS Review: Surgery, Radiation, and Prevention. Laura Esserman M.D.,M.B.A. Director, UCSF Carol Franc Buck Breast Care Center Professor of Surgery and Radiology. Abstracts. Surgical Practice Patterns (12) Surgical Techniques (406) Local Recurrence (29, 7,8) Sentinel Nodes (20,21)

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2005 SABCS Review: Surgery, Radiation, and Prevention

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  1. 2005 SABCS Review: Surgery, Radiation, and Prevention Laura Esserman M.D.,M.B.A. Director, UCSF Carol Franc Buck Breast Care Center Professor of Surgery and Radiology

  2. Abstracts • Surgical Practice Patterns (12) • Surgical Techniques (406) • Local Recurrence (29, 7,8) • Sentinel Nodes (20,21) • Prevention (36)

  3. Surgical Practice Patterns (12) • Surgical biopsy as a diagnostic tool adversely affects outcomes of breast cancer care • National Comprehensive Cancer Centers Network Edge et. al. • 6282 women, 8 centers, 1997-2002 • Outcomes • Re-excision, total trips to the OR, elapsed time to complete surgical care • Re-excision rate associated with initial biopsy (83% higher) • Re-excision affects time to complete surgery • Mean time to complete surgery 30 vs. 48 days • Includes initial biopsy

  4. Total Skin Sparing Mastectomy • Nipple and areola complex dermis can be preserved (63 cases) • Different techniques analyzed • Lateral incision most reliable • Expect skin sloughing, but dermis will regenerate • MRI used to avoid tumor present under nipple • Pathology sectioning identified 2 cases with DCIS (microscopic) in excised nipple tissue • Cosmetic results excellent • Technically challenging

  5. Figure 2: Types of incisions used SS/FG TSS/N A B D E C TSS/I TSS/M TSS/R

  6. Figure 3: Total skin-sparing mastectomy pathology specimen B A C

  7. Figure 4: Post-operative successes B A R L C D

  8. Local Recurrence Biology predicts local recurrence tumor biology age, breast density

  9. Gene Differences Predict Local Recurrence • Confirms that biology drives both local and distant recurrence • Suggests, however, that some features drive local recurrence alone and not distant recurrence

  10. Association Between the 21-Gene Recurrence Score Assay (RS) and Risk of Loco-Regional Failure in Node-Negative, ER-Positive Breast Cancer: Results from NSABP B-14 and NSABP B-20 Eleftherios Mamounas,1,3 Gong Tang,1 John Bryant,1 Soonmyung Paik,1 Steven Shak,2 Joseph Costantino,1 Drew Watson,2 D. Lawrence Wickerham,1 and Norman Wolmark1 1NSABP Operations and Biostatistical Center, Pittsburgh, PA 2Genomic Health Inc, Redwood City, CA 3Aultman Health Foundation, Canton, OH

  11. Background PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 • The 21-Gene Recurrence Score (Oncotype DX) is an RT-PCR based gene expression profiling assay that includes 16 cancer genes and 5 reference genes. HER2 GRB7 HER2 INVASION Stromelysin 3 Cathepsin L2 CD68 BAG1 GSTM1 REFERENCE GENES Beta-actin, GAPDH, RPLPO GUS, TFRC

  12. Background (cont.) NSABP B-14 Validation Study • The RS has been shown to quantify risk of distant recurrence in node-negative, ER-positive, tamoxifen-treated breast cancer patients and has been validated in two independent data sets (Paik et al., 2005, Habel et al., 2004) Paik S, et al: N Engl J Med, 2005

  13. Statistical Considerations (cont.) • RS categories were defined as in previous studies on distant recurrence: • Low RS: < 18 • Intermediate RS: 18-30 • High RS: > 31

  14. NSABP Node-Negative, ER-Positive Trials B-14: Placebo vs. Tamoxifen B-20: Tamoxifen vs. MFT vs. CMFT B-14 Registry: Tamoxifen

  15. Patient CharacteristicsSurgery Type • All lumpectomy patients received breast XRT • Post-mastectomy chest wall XRT was not allowed • Regional nodal XRT was not allowed irrespective of surgical procedure

  16. Results • Based on the Ten-year K-M Estimate of LRF Rate According to RS Category • Tamoxifen-Treated Pts from B-14 and B-20 (n=895) • Placebo-Treated Pts from B-14 (n=355) • Chemotherapy + Tamoxifen-Treated Pts from B-20 (n=424)

  17. 10-Year LRF Rates According to RS Category Tamoxifen-Treated Patients (B-14/B-20, n=895) 40 RS < 18 RS 18-30 RS >31 30 P<0.0001 Rate of LRF % 20 15.8 7.2 10 4.3 0 0 2 4 6 8 10 Time in Years

  18. 10-Year LRF Rates According to RS Category Placebo-Treated Patients (B-14, n=355) 40 RS < 18 RS 18-30 RS >31 30 P=0.022 20.0 Rate of LRF % 20 18.4 10 10.8 0 0 2 4 6 8 10 Time in Years

  19. 10-Year LRF RatesAccording to RS Category Chemo + Tamoxifen-Treated Patients (B-20, n=424) 40 RS < 18 RS 18-30 RS >31 30 P=0.028 Rate of LRF % 20 7.8 10 2.7 1.6 0 0 2 4 6 8 10 Time in Years

  20. P=0.022 P<0.0001 20 18.4 15.8 P=0.028 10.8 7.8 7.2 4.3 2.7 1.6 Placebo n=355 TAM n=895 Chemo + TAM n=424 10-Year LR Failure Rates According to Treatment and RS Category 40 % RS < 18 RS 18-30 30 RS >31 20 10 0

  21. Cox Proportional Hazard ModelsTAM-Treated Pts (n=895)

  22. Multivariate Cox Proportional Hazard ModelsTAM-Treated Pts (n=895)

  23. 10-Year Loco-Regional Failure Rates TAM-Treated Pts with Mastectomy (n=505) • XRT overview suggests that there is a 1% decrease in mortality for every 5% difference in local recurrence • biology and density may contribute to decisions about XRT even after mastectomy

  24. 10-Year Loco-Regional Failure Rates TAM-Treated Pts with Lumpectomy/XRT (n=390) Lower rates of recurrence in postmenopausal women suggest that partial breast radiation is likely to be most effective in that group

  25. Biology • Biology, as measured by recurrence score, or grade, and age, predicts local recurrence. • Women<50 with mastectomy had high local recurrence if RS high • Women>50 with mastectomy had low local recurrence rates • Women <50 with lumpectomy had higher local recurrence if RS >18 • Supports recurring observation of high LRF in young women, but refines it based on biology of tumor • Opportunity may be to look at the interaction of stroma and tumor to predict Local Recurrence

  26. XRT benefits depend on age and tumor type • Abstract 7: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ (DCIS): 10 year results of EORTC randomized trial 10853 Bijker et al • 1010 women randomized to XRT vs not, 50Gy (5wks) • Tumors <5cm • Detection:Clinical (30%) or Mammographic (71%) • Median F/U 10.2 • LR 75% vs. 85% , no RT vs. RT • DCIS and invasive cancer equally reduced • No difference in metastatic disease, OS • Highest Risk for LR with Breast Conservation • Women < 40 HR =1.95 • Positive margins HR= 1.82 • Clinical Detection HR=1.53 • Grade 3,2 vs. 1 HR=1.77, 1.3 • Solid, cribriform vs. micropapillary, clinging HR=2.21, 2.28 • Lumpectomy alone vs. RT HR=1.74

  27. XRT benefits depend on age and tumor type • Abstract 8: Breast Conservation without radiotherapy in low risk breast cancer patients- results of 2 prospective clinical trials of the Austrian Breast and Colorectal Cancer Study Group involving 1,518 postmenopausal patients with endocrine responsive breast cancerGrant et al • XRT in ER+ postmenopausal women: OS not different, 11 fold decrease in LR, but absolute difference in 3% range • Local Recurrence Rate 5.2 vs. O.4 with XRT vs. not (all patients) • Randomized Trial (ABCSG-8): Median FU 121 months • Overall survival: No difference • Overall LR 1.71% (No RT 0.24 vs. RT 3.19%)

  28. DCIS RT does not affect OS Biology may predict LR and impact of RT Option of using RT for LR failure Think about Prevention first?

  29. Invasive Cancer Should biology be the guide for choosing RT, targeted RT, or nothing?

  30. Sentinel Nodes

  31. Issues Addressed • NSABP B-32 • If you find a sentinel node that is positive, what is the likelihood of finding other positive nodes? • Depends on how many sentinel nodes are positive • Depends on the total number of nodes removed • Moffit South Florida Cohort Study • If you find microscopic tumor in a node, IHC+ or H&E+ (<2mm) what does it signify? • That you have a 12-15% risk of macroscopic tumor in other lymph nodes • Impact on survival determined by the presence of true H&E positive disease

  32. Significance of Sentinel Lymph Node Micrometastasis on Survival for Patients With Invasive Breast Cancer Charles E. Cox, M.D. J Cox, M.D., A Riker, M.D., L White, B.S., D Hasson, B.S., N Allred, D Ramos, M Myers, E Dupont, M.D., J King, B.S., A Cantor, Ph.D., V Vrcel, M.D., N Diaz, M.D., N Draper, M.D., C Schuetz, M.D., and S Khera, M.D.

  33. Abstract 21 6781 patients No n=2762 N1+ n=3047 N? n=227 • N0(i+): 15/116 12.9% • N1mi : 17/111 15.3% _______________________________ • Total: 32/227 14.1%

  34. Results: T-Stage Comparison Overall Survival Comparison by T Stage For N0(i-) Patients P = 0.008

  35. Results • T1-T3 N1mi patients F/U > 5yrs had significantly worse OS (p=0.005) and DSF (p=0.016) than T1-T3 N0(i-) pts. • T1 N1mi patients show a significantly worse OS than T1 N0(i-) pts. (p = 0.04) at 2yrs of F/U THESE DIFFERENCES DISAPPEARED WHEN MACROSCOPIC CASES ARE REASSIGNED • T2 N1mi patients OS is not significantly worse than T2 N0(i-) pts. (p = 0.14) ( T size and F/U may be factors)

  36. Practice Changing (-) no ALND N0 N0 (i+) N1 mi SLN ALND (+)ALND N1

  37. Continued Technical Results of NSABP B-32: Does a Positive Sentinel Node Biopsy Always Require an Axillary Dissection? Thomas B Julian MD, Stewart Anderson PhD, Ann Brown ScD, Harry Bear MD, David Krag MD, Seth Harlow MD, Taka Ashikaga PhD, Donald Weaver MD, Barbara Miller RN MSN, Lynne Jalovec MD, Thomas Frazier MD, Richard Dirk,Noyes MD, Andre Robidoux MD, Hugh Scarth MD, Denise Mammolito MD, David McCready MD, Eleftherios P Mamounas MD, Joseph Costantino DrPH, John Bryant PhD, and Norman Wolmark MD NSABP Operations and Biostatistical Centers, Pittsburgh PA Department of Surgery University of Vermont, Burlington VT San Antonio Breast Cancer Symposium December 9, 2005

  38. Clinically Negative Axillary Nodes • Stratification • Age • Clinical Tumor Size • Type of Surgery NSABP B-32 Randomization GROUP 1 Sentinel Node Resection* Followed By Axillary Dissection GROUP 2 Sentinel Node Resection * Path. Neg. Sentinel Node Path. Pos. Sentinel Node Axillary Dissection No Axillary Dissection

  39. NSABP B-32Sentinel Node Identification/Evaluation • Combined technique of isotope, dye, and palpation for identification • Sectioned at 2-3 mm intervals • 5m sections for H&E stains

  40. NSABP B-32 • SN identification rate: 97.1% • SN positive rate: 26% • False negative rate: 9.8% • Average SNs: 3.0 • SLNs were the only positive node in 61.4% of node positive patients

  41. Question Can factors be identified which predict for positive non-sentinel axillary nodes (PNSN) in AND specimen following a positive SN biopsy?

  42. Study Design • 5,611 patients randomized with 2,807 in the SNR/AND Group 1 and 2,804 in the SNR Group 2 • 1,361 patients had a positive SN and AND in both Groups combined • 1,355 of these patients underwent multivariate analysis

  43. Univariate AnalysisFactors Associated with Positive NSN

  44. Univariate AnalysisFactors Associated with Positive NSN † p-value for test of trend ‡ p-value for test of heterogeneity

  45. Univariate AnalysisFactors Associated with Positive NSN §Six values are unknown †p-value for test of trend‡p-value for test of heterogeneity

  46. Univariate Factors not Significant Predictors for Positive NSN • Age • Type of biopsy • Histologic grade • ER/PR status

  47. Multivariate Analysis Logistic model of proportion of patients who are NSN Positive † Baseline for comparison *Removed is the Number of NSN ‡Odds ratio for increase of one unit §Modeled as continuous variable

  48. 0.7 1 SN 0.6 0.5 3 SN 0.4 Probability of Positive NSN 5 SN 0.3 7 SN 0.2 9 SN 0.1 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Clinical Tumor Size (cm) Predicted Probability of a Patient with Positive NSN as a Function of Clinical Tumor Size and the Number of Sentinel Nodes Removed with One Positive Sentinel Node UOQ 1 PSN 1 Hot Spot

  49. Predicted Probability of a Patient with Positive NSN as a Function of Tumor Size and the Number of Positive Sentinel Nodes with 5 Sentinel Nodes Removed 1 SN 5+ 0.9 SN 4+ 0.8 SN 3+ 0.7 0.6 SN 2+ Probability of Positive NSN 0.5 0.4 SN 1+ 0.3 UOQ 1 Hot Spot 5 SN Removed 0.2 0.1 0 0 1 2 3 4 5 Clinical Tumor Size (cm)

  50. Conclusions No subset of patients could be identified that had a sufficiently low probability for PNSN to allow for omission of AND unless the number of sentinel nodes removed approached that of an axillary dissection. These results support the need for AND with PSN by H&E for staging and treatment planning. Analysis of the NSABP B-32 sentinel node negative patients by IHC may yet identify patient populations where AND can be avoided.

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